Q&A: What Can Hormone Replacement Therapy Do for Brain Health?

Hormone replacement therapy (HRT) for estrogen — the use of pills, topical gels, and other applications to supplement estrogen production — is used to treat symptoms associated with female menopause. But is it beneficial to menopause’s cognitive symptoms? And, could it have protective powers for brain health that stretch beyond menopause’s immediate symptoms? That is the question that Dr. Eef Hogervorst has spent much of her career investigating. 

Dr. Hogervorst, a professor of Biological Psychology at Loughborough University in the United Kingdom, studies dementia risk factors and prevention. She first began looking into the role of estrogens and HRT — also known as menopausal hormone therapy or postmenopausal hormone therapy — in cognitive function for women in the 1990s. As people go through menopause their bodies tend to produce less estrogen. At the same time, many people going through female perimenopause tend to experience cognitive symptoms, such as brain fog — an all-encompassing term used to describe a set of symptoms including forgetfulness and an inability to focus. Could replacing the lost estrogen help prevent that cognitive decline? What Hogervorst saw in her early research was promising, she said. Women in the study who took estradiol, a natural estrogen rather than an estrogen derived from horse urine, experienced a complete turnaround in their cognitive symptoms. That early research inspired her to continue looking into estrogen by conducting future studies of her own and analyzing those of others.

While, based on her research, Hogervorst believes most women in perimenopause should try HRT, even if it’s just by taking over the counter phytoestrogens — supplements or foods that contain a substance found in some plants that is similar to estrogen made by human bodies –– she’ll be the first to admit that there are still unknowns and the data from many observational studies looking into the role of estrogen in dementia prevention and overall cognitive health are inconclusive. 

However, she notes, there is no simple answer for who should start it, when to start it, what type of estrogen to take, how long to do it for and how much of an effect it will have both short and long term, and it is not right for everyone. Along with these unknowns, there are also the risk factors that have to be considered, such as possible increased risk of certain health conditions including bleeding, incontinence, and even blood clots or breast cancer under certain conditions.

As part of our LiveTalks series, Being Patient spoke with Dr. Hogervorst about HRT, the different types of estrogens available, who should try HRT, the potential of this treatment, and the various issues with the research around it so far.

Being Patient: What do we know about the relationship between the amount of estrogen we produce and the brain?

Dr. Eef Hogervorst: During menopause, our hormone levels have gone down, but before that, in perimenopause, what we see is hormone fluctuations. Estrogens go up. They go down. Your progesterone is all over the place. Hormones make you hungry, they make you sleepy, they make you lose weight, they can make you gain weight, and estrogen affects all those hormones that do that. An enormous amount of research has been done and estrogens can really affect the brain in so many ways — anything to do with cognitive aging, memory loss, dementia — and animal studies and cell culture studies have found that estrogens can exert benefits on that. That’s what we call biological plausibility and it’s huge. Estrogen should really protect the aging brain. 

But the problem is we have observational data showing us that women who use hormones are already often protected against dementia. They have a lower risk of heart-related health conditions, which reduces the risk of dementia. But women who use hormones also have a lot of other characteristics that protect them against dementia. They have money to buy estrogens and they also have money to buy better foods. They tend to be educated which is a huge protective factor against dementia. They have knowledge; they eat really well; they have lower blood pressure they do everything to protect themselves against dementia so it’s quite difficult to disentangle that from using hormones for menopausal complaints. 

So, then, we need to look at treatment studies. I did Cochrane analysis for some time, which is like the gold standard for meta-analysis, looking at all these studies. What we saw was that hormones can improve function, memory function, speed of information processing, complex function for a very short period of time especially in women who have a lot of symptoms. Because if you’re not sleeping and you’ve got a lot of hot flushes and you feel very uncomfortable that will impact your ability to concentrate and focus. And so we see that, for those women in particular, we see that hormones can really benefit your ability to focus again and to improve your memory. But those effects are usually in the treatment trials. When we compare it to placebo short term, they are only there for a couple of months. And then what we see is after a year these effects start reversing back to baseline. And then if women are older and they start taking these, say 65, which is approximately 15 years after the age of menopause, we see that some women seem to actually be getting worse.

Professor Roberta Diaz Brinton, who’s a great expert in this area and who wrote a book with a us called “Hormones, Cognition, and Dementia,” found that if we expose brain cells to estrogens and if these cells have damage which we associate with worse function — damage to the mitochondria, the little energy factories in the brain, and damage to calcium channels which are really important in aging — estrogen will make that damage worse. And so in 2003 the Women’s Health Initiative study came out showing that older women who hadn’t been using hormones over the age of 65, who were at risk for dementia, and who took hormones started having more risk for dementia after a year. So this was a great shock! 

Being Patient: When women approach perimenopause, there’s a fluctuation of hormones. Some people fall off a cliff, for other people it’s more gradual. If you fall off a cliff, is that more risky to your brain?

Dr. Eef Hogervorst: What Pauline Maki’s group, a wonderful expert in this area, found was that 23% of women really have measurable problems with memory and brain function. Some of them get better, other women get worse. And in some of her studies she found that having worse sleep was associated with having worse symptoms. But, to my knowledge there are studies that have found benefits to women who do not have severe symptoms. It’s not entirely clear what that’s associated with because if you look at the levels, the estrogen levels, it’s not that necessarily clear either — it’s perhaps your own sensitivity to estrogen levels. 

Being Patient: Do we know how estrogen impacts the brain? What’s the relationship between the levels of estrogen we have and our brains?

Dr. Eef Hogervorst: If you look at animal studies where you can manipulate that a little bit easier, we see that if estrogens are withdrawn, you see massive effects. Estrogens can stimulate the branching of dendrites, so the contact between the brain cells, the neurons. They can promote neurotransmitters, so the chemical messengers that are important for the talking between the cells. So that can affect your mood. It can affect the speed of information processing. Estrogens can affect access of oxygen to the brain, and the use of oxygen and glucose from the blood in the brain. And one of the other factors that are becoming increasingly more important for dementia is inflammation, low grade inflammation in the brain. Estrogens can also protect against that. But, as I said, they also have effects on all these other hormones –– thyroid hormones, growth hormones, insulin. They have so many other effects on other hormones that affect your body and your brain. 

Being Patient:  Should a woman who is approaching menopause and showing some perimenopausal symptoms consider HRT? You mentioned that there is proof that there are short-term benefits for people before they go through menopause. Is that correct? What do we know about that?

Dr. Eef Hogervorst: That’s right. Absolutely. I think if you are suffering, you should have a discussion with your general practitioner. And if they don’t want to go there, you should find another general practitioner. 

One of the problems is the perceived breast cancer risk and we really need to put that in perspective. Yes, there is a slight increase in breast cancer risk but that’s about comparable to drinking wine. A lot of women our age like a glass of wine and they don’t see any issues with that. Now we know that that slightly increases your risk of breast cancer but it’s nothing compared to the risk, for instance, of being overweight. Estrogens can possibly help you not gain fat around the midriff, because that’s one of the things that starts happening after menopause. And that is a big risk factor for low grade inflammation, heart disease, and for dementia in later life. 

Whether estrogens help or not, I don’t know. But what they certainly will help with in some women –– quite a lot of women, about 50% of women –– is they feel a lot better. Their mood improves, and their concentration improves. If you have symptoms, try it. 

Being Patient: What are the questions that women should be asking their general practitioners or their doctors in order to figure out if they’re the right candidate for HRT?

Dr. Eef Hogervorst: There’s a number of contraindications. There are things that make it tricky but perhaps not impossible. In the past if your mom had had breast cancer, they would say, “Forget it, don’t do it.” Now I think you need to be cautious. You might want to have yourself tested, but again, it’s a little bit debated whether that should be done or shouldn’t be done. These days a lot of the guidance stipulates that if there is a risk for breast cancer in the family you can consider it unless if it’s the BRACA gene. My mom had breast cancer but I’m taking HRT and I’m monitoring that. 

Being Patient: What is the indicator to determine whether or not this is a treatment we should consider?

Dr. Eef Hogervorst: That’s a really interesting question because hormones of course fluctuate over the cycle if you’re not taking birth control pills. And in the years before menopause, you’re all over the place. 

A lot of women shop around quite a bit. A lot of women like estrogel, which is a gel you can put on your thighs and you can kind of regulate how much feels good. Like too much, you might feel nauseous, your breast starts hurting. You might want to reduce that level a little bit. With estrogel, you can do that. You can reduce the level. And the risks for breast cancer with the gel are much less because it doesn’t go through the liver. It just gets absorbed into the blood. It very much acts like your ovaries would do with a natural estrogen so it’s not like the horse urine metabolites used in the treatment called Premarin..

Being Patient: Just to clarify, this is a gel versus a patch?

Dr. Eef Hogervorst: The patches are pretty good as well. They do the same as the gel but they are perhaps less easy when to decide your own dose. I certainly wouldn’t exceed the maximum dose. For instance, I myself have reduced that dose. I didn’t feel good with the prescribed dose. A much lower dose was better. 

The other one I’m talking about which you probably shouldn’t do but some women do benefit from it is Premarin. That’s the horse urine metabolite derived estrogen so it’s not a human estrogen. Some women do benefit from it but I’ve never seen that improve cognitive function in the treatment trials. 

Being Patient: You were talking about two types of estrogens — the estradiol, which is in the gel, and Premarin, which is the horse urine one. The estradiol type of estrogen, what do we know in terms of improvement? Is this based on studies where women say, “I’m approaching menopause, or going through menopause, I have brain fog.” Is that the type of symptom that estradiol could possibly correct?

Dr. Eef Hogervorst: It could potentially do so. We’ve done a meta analysis where we saw it and it worked for a couple of months. Women felt better. I did a study myself in the ’90s where the difference was stunning. Women would use estradiol — you can also take it orally because in those days general practitioners preferred to give it orally rather than in the patch — and these women when I assessed them at baseline they would be crying, they had memory issues, they had name recall problems. And after taking the estradiol, I was stunned by the benefit. A lot of people said, “Why do you continue to research this?” Because as a young student 30 years ago I saw it had an effect. These women were suddenly playing tennis again. They were happy. The effect was amazing. 

But we shouldn’t forget that about half of women who start HRT and say, “It didn’t do anything for me. I didn’t like the side effects.” If you have symptoms, it’s worth a shot. What I would suggest you do is first try natural ways of supplementing estrogen: phytoestrogens, black cohosh. They have less of an effect. About half of the effect on reducing the hot flushes. Their effect on memory improvement is questionable but some women do find benefit. 

Being Patient: Why is it that many women who are on estradiol or taking HRT also take progesterone. Is that related to the brain at all?

Dr. Eef Hogervorst: If you have an intact womb, you have to take a progesterone for at least half of the month because otherwise your risk of developing endometrial cancer is really high. You don’t want to run that risk. You can also put a coil in with progesterone. It’s called the Mirena Coil. But you don’t just want to take estradiol. Your GP, if you have a womb, will always prescribe progesterone. 

Progesterone has quite beneficial effects on the brain in that it acts as a calming agent. It acts on the same neurotransmitter so it can make you calm and improve your sleep. A lot of women take it before they go to bed. 

But if we look at your observational data, the biggest improvements we’re seeing in women over time, if there is any protective effect, and a large UK study showed that, was in women who only used estradiol. Now those are women without a womb. And what we know is that the earlier the womb and the ovaries are taken out, the worse the effect is on increasing dementia risk. So those women do have an increased risk for dementia. Most of the data suggests — we wrote a European report about this a couple of years ago — that they should really try to reduce their risk for dementia through lifestyle, exercise, healthy diet, not smoking, but also should probably consider HRT up to the natural age of menopause around fifty. So if you don’t have a womb and you can take estrogen by itself, the estradiol, you should definitely consider it if your age or menopause is before the age of 45, certainly if it’s before the age of 40. So, if you’ve had surgery before the age of 40, your risk of osteoporosis is really high — bone loss, bone breaks, but also dementia, and heart disease. We think that those women, people should probably consider HRT. 

Being Patient: How long should women stay in HRT?

Dr. Eef Hogervorst: Looking at the data, we showed that by a year most of the benefits on brain function have disappeared. So it’s very nice to carry women over that period with loss of sleep and all these symptoms and once that’s calmed down, you know that change to help you adapt to the next phase. You can stop it at any time of course.

But, the data also suggests that for women using it up to about five years after menopause, it will not increase the risk for breast cancer so much. But if you continue using it over seven years, 10 years, the longer you use it, the more of an increased risk of breast cancer you have.

So, a lot of guidelines say please don’t use it for longer than five to seven years. But again this probably depends on your health status and your risk. If you’re obese, you drink a lot of alcohol, you smoke, you have a family risk of breast cancer, you might want to be even more careful. But if you’re fit, you’re healthy, you take care of yourself — I’ve spoken to gynecologists who have people who are in their seventies and don’t want to stop taking it. And so weighing up that risk and benefit is quite difficult I think. 

Being Patient: What do we know exactly based on research studies about reducing the risk of dementia and taking HRT to date?

Dr. Eef Hogervorst: We wrote a book about this with all the world’s experts on what can you do to prevent dementia. Basically the bottom line is that what is good for your heart is good for your brain. Risks are obesity, being inactive, having high blood pressure, high cholesterol, being at risk for diabetes or having diabetes, smoking, and at various stages of your life that risk is very much increased, especially in midlife.

Midlife is probably a time when you should really do something about it, really think about reducing your dementia risk. Before that, you can do a lot. As a youngster you can do an awful lot of damage to your body and there’s a lot of regenerative capacity. But as we get to midlife, 45, this is the time to stop that. You really want to stop smoking and you want to make sure that because as we age, unless we’re very active, we start losing muscle mass and we start gaining fat. We know that that’s really important to tackle to reduce dementia risk. 

Now, the problem with the observational studies which showed the reduced dementia risk in sharp contrast to those treatment studies that only showed at best very short-term benefits, the observational studies can show benefits, especially with the estradiol only. And the problem is that women who undergo natural menopause, studies have found that years before they decide to take the hormones, they were already healthier. They exercise, they have the knowledge, they eat well, they’re doing everything to protect their heart, and with that, they’re protecting the brain. So to disentangle that is like what’s causing what?

Hormones could certainly perhaps cause additional benefit. But then, why don’t they do it in the treatment trials? They don’t. So on some parameters, yes, but it’s not very consistent data. But on the other hand, women undergoing early menopause, who’ve had their ovaries taken out, those women should probably consider it because that early loss of estrogens could be very detrimental. That could really accelerate your aging process. Because of the effect estrogens also have on your other hormones and your body in general. 

Being Patient: What is the next phase of all of this research?

Dr. Eef Hogervorst: I came to Loughborough because it’s the most well-known university in the world for sports and exercise. I came here to look at exercise programs that we could develop to prevent dementia. These are very low key, 20 to 30 minute exercises a couple times a week to improve brain function. They definitely improve memory function in middle aged people, in older people with and without dementia, and also in women who have undergone surgical menopause. However, we found that low intensity exercises like resistance band exercises and exercises that make sure you get outside like walking, where you’re exposed to the elements and have all that sensory input, and moving your body is very important.  

The other thing that we’ve been looking at is effective nutrition. I’m partly Indonesian and I’ve gone there a lot and we looked at tofu and tempe because these are soy products and they are high in estrogen. And what we found that there were some benefits of tofu for middle age but like the estrogens, they were very short term. But we found another product which is consumed in Indonesia called tempe. It’s the whole soybean and it’s fermented. And in its fermentation it produces a lot of antioxidants, and immune promoting substances. It also has a lot of fiber so it can reduce cholesterol, it stabilizes your blood glucose. We tested in animals and in humans.

We found that in the brains of rats where we took the ovaries out, that plaques, the amyloid plaques we see in dementia, shot up after the ovaries were taken out. So the rats were at much higher risk for dementia. But if those rats were given tempe or estrogens, with estrogens those plaque levels went down to normal levels. But with the tempe those levels dropped way below the baseline. So we were doing observational studies in Indonesia and we found that the people who ate tempe had a much reduced risk for dementia as well. 

Being Patient: How much do you have to eat?

Dr. Eef Hogervorst: That’s one of the problems. It might well be that that doesn’t translate to Europeans. It helped a little bit in our UK women. We gave it to menopausal women first. First of all, tempe tastes a bit like cardboard so you have to do a lot to it to make it tasty. That’s because of the fermentation. And it’s very fibrous. It can affect your tummy and some people said they really had tummy upsets eating a lot of it. 

Now we found people need to eat 75 grams per day to have these beneficial effects. In Indonesia, people do eat that because it’s part of the staple diet like tofu. Also Indonesian people have slightly different bacteria in their gut and it is highly estrogenic. Most western people don’t produce that. So the benefits we saw in Indonesian people were much higher than in UK people. So first of all they probably can’t literally stomach it. And second of all you have to eat so much of it and then maybe not even have the benefits. 

We’re currently looking into if we can mimic this effect perhaps in other ways. Maybe by developing some sort of tablet or some other treatment with some people in Singapore. The problem is though, tempe is such a wonderful food because it doesn’t just contain phytoestrogens but lots of other stuff as well through its fermentation, and to mimic that is quite complicated. We can do it, but there’s probably over 250 different possibly beneficial compounds. Do we stick them all in? Is it cost beneficial for industry to do that? Because if you have to source all these chemicals to stick them in your pill, are you going to get the money out? At the end, we’re back to square one, which is, you should eat the natural product, but that’s not so easy. 

A lot of women try things like MenoForce which is made of sage, very estrogenic. Sage has long been prescribed to protect against memory loss — the sage plant. Again, if you drink a tea of that or eat it, it tends to aggravate your gut so the pills are probably better but again, like the estrogens, a lot of people find that beneficial for a couple of months.